Nanoparticle-integrated smart hydrogel with H2S-triggered antibacterial escalation and sustained oxygen release for periodontal regeneration

Periodontitis is a widespread chronic inflammatory disease characterized by pathogenic bacterial biofilms and a hypoxic microenvironment, which together impede effective treatment and tissue regeneration. To overcome these challenges, we developed an injectable, hydrogen sulfide (H 2 S)-responsive nanocomposite hydrogel, termed PDA@Hb/NOCG, for microenvironment-adaptive therapy. This hydrogel was formulated by incorporating hemoglobin-polydopamine nanoparticles (PDA@Hb NPs) as an oxygen-generating element and tetra-armed azide-terminated polyethylene glycol as an H 2 S-scavenging component into a dynamically cross-linked Schiff base network. The platform demonstrated satisfactory injectability, self-healing properties, and sustained oxygen release. Notably, upon encountering pathological levels of H 2 S, a key metabolite of anaerobic infection, the hydrogel underwent an azide-to-amine transformation, significantly enhancing its cationic antibacterial activity in situ. In vitro studies revealed that PDA@Hb/NOCG effectively reduced hypoxia, exhibited strong antibacterial and antibiofilm activities against Porphyromonas gingivalis , Escherichia coli , and Staphylococcus aureus , and possessed excellent cytocompatibility. Additionally, under inflammatory conditions, it promoted the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) by activating the Wnt/β-catenin pathway. In a rat periodontitis model, PDA@Hb/NOCG significantly alleviated local bacterial burden, reduced inflammatory infiltration, and maintained alveolar bone structure, as confirmed by micro-CT and histological analyses, without inducing systemic toxicity. This study presents a novel nano-enabled, gas-responsive hydrogel that executes a sequential therapeutic strategy, from hypoxia alleviation and on-demand antibacterial enhancement to pro-osteogenic activation, offering a promising, minimally invasive approach for synergistic infection control and tissue regeneration in periodontitis.